The vertebrate central nervous system (CNS) is composed of an intricate array of neural cell types that originate from both stem and progenitor cells located within the neural tube. The co-ordinated generation of this complex network of neural cells underlies the ability of the CNS to function properly. Any alteration in the development fate, or the degeneration of any one of these cell types, can lead to CNS dysfunction. The overall objective of the proposed research is to gain insight into the common molecular and cellular mechanisms that are involved in the correct differentiation of neural stem cells both during embryogenesis and in the adult animal. This work will focus on the role of three transcription factors, SOX1, SOX2, and SOX3 (the SOXB1 subfamily) in neural differentiation. In mammals, the onset of SOX1 expression and the concomitant restriction of SOX2 and SOX3 expression to the neural epithelium are coincident with neural induction. The expression of the SOXB1 subfamily is then maintained in proliferating neural epithelial cells throughout embryogenesis and into adulthood. Thus, the SOXB1 subfamily appears to mark a common transcriptional program shared by stage specific neural progenitors and provides a potential means by which to define, isolate, and characterize neural progenitor cells at different developmental stages. Moreover, our past studies provide direct evidence for a role of the SOXB1 subfamily in neural differentiation. The work outlined in this proposal involves a genetic approach in the mouse to assess the function of SoxB1 genes in embryonic and adult neural progenitors. In the long term, results from work will lead to clinical applications such as transplantation therapy in animal models of neurodegenerative diseases. Only through a thorough understanding of the cellular and molecular mechanisms will researchers be able to efficiently direct stem cell differentiation into specific cell types needed for transplantation.